Molecular Mechanisms of Patterning the Limb Proximodistal Axis and Quantitative Studies Addressing its Scalability over Five-Fold Changes in Size.

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How animals pattern and scale organ size during development is a fundamental problem in developmental cell biology that also has relevance for engineering tissues for regenerative applications. The vertebrate limb bud is an important model to examine how an appropriately proportioned upper arm, lower arm and hand along the proximal/distal (PD) axis arises but a consensus model does not yet exist. Axolotl limb regeneration provides unique experimental advantages to address this problem. Limb regeneration occurs via the same sequence of HOXA gene induction as in development but more slowly than other vertebrates and it occurs in blastemas from animals >5-fold different in size. Here we use heterochronic cell transplantation, in vivo and ex vivo perturbation of major signalling pathways and CRISPR-mediated knockout of novel apical epithelial genes to test the major limb patterning models and identify the molecular pathways governing HOXA11 and HOXA13 induction. We then use this information to test three hypotheses of how limb patterning scales over a 5-fold range in limb field size.